Trypanocidal activity of flavanone derivatives

Article abstract of DOI:10.3390/molecules25020397

Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.

Full text of DOI:10.3390/molecules25020397

molecules
Article
Trypanocidal Activity of Flavanone Derivatives
1
1
2
Gabriela Maciel Diogo , Josimara Souza Andrade , Policarpo Ademar Sales Junior ,
Silvane Maria Fonseca Murta , Viviane Martins Rebello Dos Santos and Jason Guy Taylor 1,*
2
1
1
Chemistry Department, ICEB, Federal University of Ouro Preto, Campus Universit
Ouro Preto 35400-000, MG, Brazil; gabriela.diogo1@gmail.br (G.M.D.);
josimara.souza28@hotmail.com (J.S.A.); vivianesantos@ufop.edu.br (V.M.R.D.S.)
René Rachou Institute, FIOCRUZ, Belo Horizonte 30190-002, MG, Brazil;
policarpoasjunior@cpqrr.fiocruz.br (P.A.S.J.); silvane@cpqrr.fiocruz.br (S.M.F.M.)
Correspondence: jason@iceb.ufop.br; Tel.: +55-313-559-1707
ário Morro do Cruzeiro,
2
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 13 November 2019; Accepted: 27 December 2019; Published: 17 January 2020
Abstract: Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease
by the World Health Organization. For clinical treatment, only two drugs have been on the market,
Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present
low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation
of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of
3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in
the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening
methodology was utilized that allowed for the simultaneous use of both parasite forms responsible
for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma
cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the
reference drug, Benznidazole.
Keywords:Chagasdisease; flavanones; flavonoids;Trypanosomacruzi; chromanones;invitro;nitroreductase
1
. Introduction
The Brazilian researcher Carlos Ribeiro Justiniano das Chagas discovered Chagas disease (also
known as American trypanosomiasis) in 1909 and revealed that the etiologic agent to be the parasite
Trypanosoma cruzi (T. cruzi) [ ]. Chagas disease is classified by the World Health Organization (WHO)
as a neglected disease along with dengue, rabies, African trypanosomiasis, among others [ ]. In a
recent survey conducted between 2008 and 2017, over 90% of reported cases of Chagas disease in the
world were confirmed in South America [ ]. A common form of transmission occurs through contact
of the mucosa of the open wound with contaminated feces of the triatomine bug [ ]. However,
1
2–4
5
5–7
the transmission is not only caused by direct contact with the parasite, but it can also be caused by
indirect contact occurring by ingestion of contaminated food containing feces of the triatomine bug.
Indeed, studies suggest that the most probable forms of transmission were oral transmission (72%),
the minority being caused by vector transmission (9%) and the remaining 19% were unidentified forms
of transmission [5].
In the acute phase of Chagas disease, symptoms like fever, discomfort, and facial edema are
common but may disappear spontaneously between four to six weeks post-infection. Treatment at
this stage is still possible, but commonly these symptoms go unnoticed and the disease transitions
many years later into the chronic phase when the heart is already severely compromised (chagasic
cardiomyopathy) and available drugs are no longer effective. Furthermore, the parasite and its major
vectors can also cause lesions in the liver and in the nervous and lymphatic systems [6].
Molecules 2020, 25, 397; doi:10.3390/molecules25020397
www.mdpi.com/journal/molecules

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Treatment of Chagas disease is restricted to Benznidazole and Nifurtimox, both of which were
introduced in the market in the 1960s and 1970s. Both of these drugs have a few drawbacks such
as: (i) moderate efficacy in the acute phase and low efficacy in the chronic phase of the disease;
(
ii) side effects such as digestive disorders, fevers, muscle pain, loss of appetite, amnesia, hematological
disorders (Nifurtimox), and hypertensive dermatitis (Benznidazole); (iii) require follow-up under
medical supervision for longer periods of time; (iv) absence of pediatric doses; (v) not being indicated
for pregnant patients. Nifurtimox was withdrawn from the Brazilian market due to its high toxicity,
making Benznidazole the only available treatment [6,7].
Many plant extracts have rendered flavonoids with anti-trypanosoma cruzi activity (Figure 1).
Ambrozin et al. isolated and evaluated the activity of two flavonoids from the leaf extract belonging to
the Rutaceae (Conchocarpus heterophyllus) family against the trypomastigote form of T. cruzi Ganapaty
et al. isolated from the roots of Tephrosia pumila (Fabaceae) Pumilanol, which displayed promising
anti T. cruzi activity and low cytotoxicity when compared to the reference compound [
isolated four flavonoids (4 -O-Methylscutellarein, Sakuranetin, Hispidulin, and Pectolinaringenin)
8
]. Grecco et al.
0
from the Baccharis retusa (Asteraceae) plant and found two of these flavonoid compounds to be more
potent than the reference drug [9–12]. Marin et al. isolated quercetin glycosides from Delphinium
gracile (Ranunculaceae), which were also evaluated against the amastigote form of Trypanosoma cruzi.
Although this compound displayed high trypanocidal activity, it was more toxic than the reference
drug compound [13].
Figure 1. Structure of flavonoids with anti-Trypanosoma cruzi activity.
The aforementioned studies have shown that flavonoids exhibit promising trypanocidal activities.
Thus, motivated by the negative economic and social impact caused by Chagas disease, lack of
alternative chemotherapies, especially in the chronic phase and the existence of naturally resistant T.
cruzi strains, this work describes the synthesis and trypanocidal activity of 3-benzoyl-flavanones.
2
. Results
2
.1. Synthesis of 3-Benzoyl Flavanones
Esterification of 2-hydroxyacetophenones with substituted benzoyl chlorides afforded initially the
corresponding esters, which were immediately subjected to a Baker–Venkataraman rearrangement
in the presence of KOH to afford the desired 1,3-diketones . All of the ester and 1,3-diketone
1

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intermediates are known compounds and were, therefore, confirmed by comparison of their NMR
spectral data and melting points with literature values (see experimental section).
Subsequently, 3-benzoyl-flavanone derivatives 2a
condensation intramolecular oxi-Michael reaction between
–
β
z
were synthesized by a domino aldol
-diketones and aldehydes in the presence
of morpholine (Scheme 1). In total, 28 3-benzoyl-flavanone derivatives were obtained in satisfactory
yields ranging from 30 to 97%, and 16 of these are unpublished compounds (Figure 2). In order
to determine what, if any, the importance of an aryl group at position 2 would play in the overall
trypanocidal activity of the target compounds, 3-benzoyl-2-methylchroman-4-one
3 was prepared by
reacting 1 with acetaldehyde (Scheme 1).
Scheme 1. Synthetic route for the preparation of flavanone derivatives: (
KOH, 50 C, 1 h; (iii) morpholine (10 mol%), ethanol, reflux, 1 h.
i
) pyridine, rt, 1 h; (ii) pyridine,
◦
All flavanone derivatives were characterized by infrared (IR) spectroscopy, H and 13C Nuclear
1
1
Magnetic Resonance spectroscopy, and high-resolution mass spectrometry. In the H NMR spectrum,
3
-benzoyl-flavanones characteristically display two doublet resonances corresponding to the methine
hydrogens present at the dihydropyranone ring (~5.17 ppm and 6.02 ppm, respectively). Rao et al.
described the synthesis of both cis and trans 7-methoxy-2,3-dimethylchroman-4-one and showed that
the coupling constant for the cis compound to be approximately 3.4 Hz and the trans being larger
around 11.5 Hz [14]. The trans configuration was, therefore, attributed to compounds 2a–z based on
comparison of their coupling constants with similar compounds in the literature given that the coupling
1
constant for 3-benzoyl-flavanones was 12 Hz. Notably, the H NMR spectra for compounds 2y and 2z
were in solution observed exclusively in their keto-enol tautomeric form (Scheme 2). The presence of a
furan ring possibly favors form
B by stabilization of an intramolecular hydrogen bond between the
furan oxygen and enol hydroxyl group (Scheme 2). The enol form for similar 3-benzoylchromanones
has also been observed in CDCl by other groups [15,16].
3
It is well established that both Benznidazole and Nifurtimox are prodrugs that require the
enzyme nitroreductase for their trypanocidal effects. For this reason, compound 2z was synthesized
bearing a nitrofuran for the purpose of evaluating possible improvement in activity via a known
biological mechanism of action. In order to maintain equivalency with Nifurtimox, the nitro group was
introduced to position 5 of the furan ring. Furthermore, compound 2a was alkylated with iodoethane
and converted to compound 4 to afford a flavanone with greater lipophilic character (Scheme 3).
Given that tricyclic compounds have demonstrated excellent trypanocidal activities [17
the chromenopyrazol was obtained by condensation of hydrazine with 2a (Scheme 4) and evaluated
for anti-T. cruzi activity.
,18],
5

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Figure 2. Synthesized 3-benzoyl-flavanones.
Scheme 2. Equilibrium for keto–enol tautomerism.

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Scheme 3. Alkylation of compound 2a.
Scheme 4. Synthesis of compound 5.
Thus, with the target compounds in hand, in vitro bioassays using trypomastigote and amastigote
forms of Y-strain T. cruzi were carried out.
2
.2. Evaluation of In Vitro Anti-T. cruzi Activity
Flavanone derivatives were evaluated for anti-T. cruzi activity against the intracellular forms of
the parasite. Although the use of epimastigotes present in the midgut vector may be utilized for initial
screening [19 20], we have instead opted for the simultaneous use of trypomastigote and intracellular
amastigotes forms that are present during both acute and chronic phases of the disease [21 22]. This
,
,
approach is in accordance with the Drugs for Neglected Diseases Initiative guidelines (DNDi) [23].
Moreover, it also has the advantage of evaluating bioactive compounds in infected cells while at the
same time monitoring their effects on both the relevant forms of the parasite in the same system.
Benznidazole was used as a positive control against T. cruzi and cytotoxicity was determined in
mammalian L929 cells (Table 1). The bioavailability profile of the flavanones was evaluated by applying
the Lipinski rule and data related to the risk of toxicity (mutagenicity, tumorigenicity, irritability, and
effects on the reproductive system) carried out through online programs “Molinspiration” and “OSIRIS
property explorer” (Table 1). The majority of the tested compounds displayed in varying degrees
some anti-T. cruzi activity and only 6 of the 29 compounds tested were found to be inactive. Initially,
compound 2a was evaluated for trypanocidal activity and this result used for comparison in order to
assess structure–activity relationships. The 50% inhibitory concentration (IC ) for 2a (8.8 µM) was only
50
slightly less potent than Benznidazole. Nevertheless, this preliminary result motivated us to investigate
other analogs bearing substituents in order to improve potency and selectivity. The importance of the
aryl group at the 2-position was demonstrated by comparison of trypanocidal activity of compounds 2a
and
reason, the aryl group was maintained or substituted for other heteroaromatic moieties. Compounds
all possess a benzoyl group at the 3-position but bear different substituents at the aryl group
3. Indeed, the absence of the benzene ring resulted in a completely inactive compound and, for this
2a–f
located at the 2-position. Among these, only the introduction of an anisole moiety (2d) significantly
improved anti-T. cruzi activity, resulting in a doubling in potency when compared to 2a. Moreover,
the selectivity of 2d was almost 4 times greater than 2a. The importance of methoxy substituents
for trypanocidal activity has been noted in other studies [17,24]. In the case of tricyclic coumarins,
a 6–7-fold improvement in trypanocidal activity was observed with the introduction of methoxy
substituents. These compounds resembled more closely the chemical structure of the trypanocidal
natural product (brevifolin carboxylate) that these structures were based on [17]. Some enhancement in
the trypanocidal activity of hybrid coumarin-chalcone compounds was also noted when the methoxy

Molecules 2020, 25, 397
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groups were introduced into either the 2 or 5 positions of the benzene ring [24]. The inclusion of a
pyridine moiety in compound 2e was supported by previous reports describing the anti-T. cruzi activity
of 2-pyridyl derivatives and their capacity to inhibit cruzain catalytic activity [25,26]. However, on this
occasion, compound 2e exhibited unremarkable anti-T. cruzi activity and was also not very selective.
No improvements in anti-T. cruzi activity were also observed for flavanones substituted at the benzoyl
moiety (2g–2o and 2v
–2x). The introduction of a methoxy or a chloro substituent at the 6-position of
the chromanone nucleus (2p
–2u) also did not provide more active compounds than 2a, although some
improvements in selectivity were observed. Given that the activation of nitroheterocyclic drugs by T.
cruzi has been shown to be associated with the formation of reactive radical species responsible for
the death of the parasite, it was no surprise that the most potent flavanone 2z (IC50 = 2.6
superior to the reference compound (3.8 M). These results are in agreement with studies showing
that in general nitrofuryl derivatives are highly potent anti-T. cruzi compounds that will often display
comparable trypanocidal activities to Nifurtimox [27 28]. The physicochemical drug descriptors of
the molecular properties for the synthesized compounds were calculated by Molinspiration software
Table 1). The majority of the tested compounds satisfy the Lipinski rule with no violations and
µM) was
µ
,
(
therefore displaying potentially good bioavailability. There were no linear correlations observed
between molecular hydrophobicity and bioactivity. All Log p-values for the bioactive flavanones were
approximately 3–4 times greater than Benznidazole and all values were less than 5, which satisfies
Lipinski’s rule of five and suggests potentially good permeability across cell membranes. Interestingly,
compound 2z presented the highest total polar surface area (TPSA) value, which is below the limit of
2
1
40 A (Lipinski’s rule) and notably was also the most closely related TPSA value to reference drug
Benznidazole. The risk of theoretical toxicity revealed that only 2z had a low risk of the mutagenic
effect but unlike Benznidazole, it was not high risk for reproductive effects.

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Table 1. In vitro trypanocidal activity, cytotoxicity, selectivity index, and physicochemical properties of bioactive flavanones.
In Vitro Activity
Lipinski’s Rule of Five
Risk Toxicity
Trypanocide
IC50(µM) ± 0.2
8.8
10.74
21.95
5.8
183.90
7.60
Inactive
22.49
24.99
63.02
29.30
223.40
37.35
212.70
26.52
Inactive
141.18
17.55
18.36
23.20
59.17
Inactive
Inactive
Inactive
113.80
2.6
Cytotoxicity
CC50(µM) ± 2.0
MW (g.mol 1)
−
Violations TPSA (A2)
Volume A3
Compound
SI
9.1
40.3
10.5
38.5
1.3
12.1
-
4.9
4.3
1
3.8
1
2.8
-
15.4
-
1.4
6.1
5.5
9.5
3.5
-
HBA
HBD
log P
4.43
NRB
M
T
I
RE
NR
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
4
5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
80
3
3
3
4
4
4
3
3
4
3
3
4
5
4
4
4
5
4
4
3
4
4
5
4
4
7
3
3
3
-
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
1
-
328.37
362.81
346.36
358.39
329.36
434.39
342.39
360.38
372.42
376.84
362.81
358.39
388.42
376.38
392.84
358.39
388.42
376.38
392.84
362.81
392.84
318.33
348.35
336.32
318.33
363.32
266.30
256.43
324.38
260.25
0
1
0
0
0
1
0
1
0
1
1
0
0
0
1
0
0
0
1
1
1
0
0
0
0
0
0
1
1
0
43.38
43.38
43.38
52.61
56.27
52.61
43.38
43.38
52.61
43.38
43.38
52.61
61.84
52.61
52.61
52.61
61.84
52.61
52.61
43.38
52.61
56.52
65.75
56.52
59.67
105.50
43.38
43.38
37.92
92.75
296.63
310.16
301.56
322.17
292.47
393.82
313.19
318.12
338.73
326.72
310.16
322.17
347.72
327.10
335.71
322.17
347.72
327.10
335.71
310.16
335.71
278.19
303.74
283.12
277.82
301.15
241.78
329.67
294.07
224.99
3
3
3
4
3
6
3
3
4
3
3
4
5
4
4
4
5
4
4
3
4
3
4
3
3
6
2
4
2
5
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
441.90
231.14
223.40
243.10
92.13
-
111.10
107.48
62.48
110.50
223.40
103.05
-
5.06
4.59
4.49
3.26
6.08
4.88
5.04
4.93
5.51
5.11
4.49
4.54
4.65
5.12
4.46
4.52
4.63
5.09
5.08
5.14
3.69
3.74
3.85
4.72
4.80
3.21
5.01
5.01
0.78
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
LR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
HR
408.10
-
206.12
106.35
102.02
220.95
204.95
-
s
t
u
v
w
x
y
z
-
-
-
-
503.0
27.54
-
449.26
38.56
2381
4.4
10.6
-
34.03
4.6
625
Inactive
13.2
8.3
NR
NR
NR
NR
Bnz
3.8
IC50: 50% inhibitory concentration. CC50: 50% cytotoxic concentration determined using mammalian L929 cells. SI: selectivity index calculated from CC50/IC50. LogP: octanol/water
partition coefficient, TPSA: total polar surface area, HBA = hydrogen bond acceptors, HBD = hydrogen bond donors, NRB = number of rotatable bonds, M = mutagenicity,
T = tumorigenicity, I = skin irritation, RE = reproductive effect, NR = no risk, LR = low risk, MR = medium risk, HR = high risk.

Molecules 2020, 25, 397
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3
. Materials and Methods
All commercial reagents were used as received. Anhydrous solvents were purchased from
Sigma-Aldrich. Flash column chromatography was performed using silica gel 200–400 Mesh. TLC
analyses were performed using silica gel plates, using ultraviolet light (254 nm), phosphomolybdic
acid, or vanillin solution for visualization. Melting points are uncorrected and were recorded on
a Buchi B-540 apparatus. For NMR data, the chemical shifts are reported in
δ (ppm) referenced to
residual solvent protons and 13C signals in deuterated chloroform. Coupling constants (J) are expressed
in Hertz (Hz). Infrared spectra were obtained on a Thermo Scientific Nicolet 380 FT-IR apparatus
−
1
(
600–4000 cm , Nicolet Instrument Corp., Madison, WI, USA) using attenuated total reflection (ATR).
Mass spectra were obtained by GC-MS, Shimadzu QP-2010 Plus model (Shimadzu, Kyoto, Japan) and
High-Resolution Mass Spectra were obtained on a Shimadzu HPLC-ESI-IT-TOF. SMILES notations of
the flavanone derivatives were inputted into an online software and subjected to molecular properties
1
13
prediction by Molinspiration software (software version v2015.01). H and C NMR spectra of these
compounds are available in the supplementary materials..
3
.1. Typical Procedure for the Synthesis of Diketones 1
In a round bottom flask (50.0 mL) equipped with stir bar, substituted 2-hydroxyacetophenone
◦
(
5 mmol), pyridine (15.0 mL), and substituted benzoyl chloride (2.5 mmol) were added at 0 C. The
reaction was allowed to warm to room temperature and left to stir for 1 h. Upon completion, the reaction
◦
was quenched with 3.0 M HCl solution (25 mL) at 0 C and the precipitate that formed was filtered
and recrystallized from hot methanol to afford esters as white solids. Next, the esters (2 mmol) were
reacted with pyridine (20.0 mL) and KOH (3 mmol) in a round bottom flask (50.0 mL) equipped
◦
with stir bar at 50 C for 30 min. At the end of the reaction, the mixture was poured into a flask
containing an aqueous solution of 10% v/v acetic acid (20.0 mL). The yellow precipitate that formed
was filtered and recrystallized from hot ethanol. All of the ester and 1,3-diketone intermediates are
known compounds and were, therefore, confirmed by comparison of their NMR spectral data and melting
points with literature values.2-acetylphenyl benzoate (1a) [29], 1-[2-(4-chlorobenzoyloxy)-phenyl]-ethanone
0
(
1b) [30], 2-acetylphenyl-4-methylbenzoate (1c) [30], 2 -(4-methoxybenzoyloxy)acetophenone (1d) [31],
benzoic acid 2-acetyl-5-methoxyphenyl ester (1e) [30], 1-[2-(4-chlorobenzoyloxy)-phenyl]-ethanone
1f) [31], 2-acetylphenyl furan-2-carboxylate (1g) [32]; 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione
1h) [33], 1-(4-chloro-phenyl)-3-(2-hydroxy-phenyl)-propane-1,3-dione (1i) [34], 1-(2-hydroxyphenyl)-3-(4-
methylphenyl)propane-1,3-dione (1j) [35], 1-(2-hydroxyphenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione
1k) [35], 1-(2-hydroxy-5-methoxyphenyl)-3-phenylpropane-1,3-dione (1l) [36], 1-(4-chloro-phenyl)-3-
2-hydroxy-phenyl)-propane-1,3-dione (1m) [34], 1-(2-hydroxyphenyl)-3-(furan-2-yl)propane-1,3-dione
1n) [37].
(
(
(
(
(
3
.2. Typical Procedure for the Synthesis of Flavanones 2a–z and 3
In a round bottom flask (50 mL), -diketone (1 mmol), substituted benzaldehydes (1.2 mmol),
β
morpholine (10 mol%), and ethanol (10 mL) were added. The mixture was allowed to stir for
◦
approximately 3 h at 70 C. Upon completion, the reaction was cooled in an ice bath until a precipitate
was formed. The product was filtered and washed with cold ethanol and finally, recrystallized with
7
0% aqueous ethanol.
Synthesis of trans-3-benzoyl-2-phenylchroman-4-one (2a): Product obtained as a white solid in 59% [38].
◦
−1
m.p.: 142–145 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3038, 2900, 1700, 1668, 1606, 1578, 1460,
f
1
447, 1231, 1031. 1H-NMR (400 MHz, CDCl3):
H), 7.09 7.13 (m, 2 H), 7.31–7.37 (m, 3 H), 7.40
.95 7.97 (m, 1 H). C-NMR (100 MHz, CDCl ):
28.8, 129.1, 133.6, 136.7, 137.1, 137.7, 161.3, 189.9, 196.1. HRMS (ESI-TOF) m/z [M
C H O : 327.1027. Found: 327.1040.
δ
5.17 (d, J = 12.0 Hz, 1 H), 6.02 (d, J = 12.0 Hz, 1
7.44 (m, 2 H), 7.50 7.60 (m, 4 H), 7.79 7.81 (m, 2 H),
59.7, 81.9, 118.2, 120.5, 121.9, 127.4, 128.6, 128.6,
H] Calculated for
−
−
−
−
13
7
1
−
δ
3
−
22
15
3

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Synthesis of trans-3-benzoyl-2-(2-chlorophenyl)chroman-4-one (2b): Product obtained as a white solid
◦
−1
in 52% [39]. m.p.: 157
1
−
160 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3054, 2925, 1689, 1658,
f
1
602, 1583, 1466, 1447, 1231, 1035, 755; H-NMR (400 MHz, CDCl ):
δ
5.45 (d, J = 12.0 Hz, 1 H), 6.44
7.48 (m, 4 H), 7.57 7.61 (m, 2 H),
57.7, 78.4, 118.1, 120.4, 122.0, 127.2, 127.5, 128.7,
3
(d, J = 12.0 Hz, 1 H), 7.10
−
7.14 (m, 2 H), 7.22
7.96 (m, 3 H). 13C-NMR (100 MHz, CDCl ):
28.8, 130.4, 130.6, 133.7, 134.1, 134.2, 136.9, 137.2, 161.2, 189.3, 195.1. HRMS (ESI-TOF) m/z [M + H]
−
7.26 (m, 2 H), 7.41
−
−
7
1
.90
−
δ
3
+
Calculated for C H ClO : 363.0782. Found: 363.0793.
22
16
3
Synthesis of trans-3-benzoyl-2-(4-fluorophenyl)chroman-4-one (2c): Product obtained as a white solid
◦
−1
in 42%. m.p.: 137–140 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3077, 2921, 1687, 1658, 1602,
f
1
1
578, 1508, 1469, 1308, 1215, 1035. H-NMR (400 MHz, CDCl ):
δ
5.12 (d, J = 12.0 Hz, 1 H), 6.00 (d,
3
J = 12.0 Hz, 1 H), 7.01–7.06 (m, 2 H), 7.11–7.14 (m, 2 H); 7.42–7.61 (m, 6 H); 7.79–7.82 (m, 2 H), 7.96
13
(
d, J = 8.0 Hz, J = 1.6 Hz, 1 H). C-NMR (100 MHz, CDCl3): δ 59.8, 81.2, 115.6 and 115.7 (d, J = 22
Hz), 118.2, 120.5, 122.1, 127.5, 128.6, 128.7, 129.3, and 129.4 (d, J = 8 Hz), 133.1 and 133.2 (d, J = 3 Hz),
−
1
33.7, 136.8, 137.58, 161.1, 161.1 and 164.1 (d, J = 246 Hz;), 189.7, 196.0. HRMS (ESI-TOF) m/z [M
−
H]
Calculated for C H FO : 345.0932. Found: 345.0930.
22
14
3
Synthesis of trans-3-benzoyl-2-(4-methoxyphenyl)chroman-4-one (2d): Product obtained as a white
◦
−1
solid in 30%. m.p.: 125
1
−
126 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3032, 2830, 1693, 1673,
f
1
605, 1587, 1515, 1469, 1255, 1047. H-NMR (400 MHz, CDCl ):
δ
3.78 (s, 3 H), 5.16 (d, J = 12.0 Hz, 1
7.12 (m, 2 H), 7.42 7.45 (m, 4 H), 7.54 7.60
55.3, 59.6,
1.5, 114.1, 118.2 120.6, 121.8, 127.4, 128.6, 128.6, 128.8, 129.3, 133.55, 136.70, 137.7, 160.0, 161.3, 190.2,
3
H), 5.96 (d, J = 12.0 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 2 H), 7.08
−
−
−
13
(
8
1
m, 2 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.95 (d, J = 8.0 Hz, 1 H). C-NMR (100 MHz, CDCl ): δ
3
+
96.2. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 359.1278. Found: 359.1296.
23 19 4
Synthesis of trans-3-benzoyl-2-(pyridin-2-yl)chroman-4-one (2e): Product obtained as a white solid in
◦
−1
6
1
1%. m.p.: 128
−
129 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3054, 2902, 1701, 1662, 1602, 1577,
f
1
515, 1462, 1300, 1219, 1034. H-NMR (400 MHz, CDCl ):
δ
5.71 (d, J = 12.0 Hz, 1 H), 6.17 (d, J = 12.0
7.61 (m, 5 H), 7.71 7.45 (m, 1 H), 7.91 7.94 (m, 1
H), 8.10 (d, J = 8.0 Hz, 2 H), 8.50 (d, J = 4.0 Hz, 1 H). C-NMR (100 MHz, CDCl ): 56.9, 81.5, 118.1,
22.0, 123.9, 123.9, 127.3, 127.8, 128.6, 129.0, 133.4, 136.6, 137.0, 137.6, 149.3, 155.2, 160.7, 189.9, 196.5.
3
Hz, 1 H), 7.07
−
7.12 (m, 2 H), 7.22
−
7.26 (m, 1 H), 7.46
−
−
−
13
δ
3
1
+
HRMS (ESI-TOF) m/z [M + H] Calculated for C H NO : 330.1125. Found: 330.1123.
21
16
3
Synthesis of trans-3-benzoyl-2-(4-(benzyloxy)phenyl)chroman-4-one (2f): Product obtained as a white
◦
−1
solid in 43%. m.p.: 128
1
−
129 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3066, 2904, 1692, 1663,
f
1
602, 1577, 1515, 1465 1265, 1238, 1075. 1029. H-NMR (400 MHz, CDCl ):
δ
5.03 (s, 2 H), 5.17 (d,
3
J = 12.0 Hz, 1 H), 5.96 (d, J = 12.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 2 H), 7.07
−
7.12 (m, 2 H), 7.36 7.46 (m,
−
13
9
H), 7.54
CDCl3):
59.2, 161.3, 190.2, 196.2. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 435.1591. Found:
−
7.60 (m, 2 H), 7.81
−
7.84 (m, 2 H), 7.95 (dd, J = 8.0 Hz, J = 1.6 Hz, 1 H). C-NMR (100 MHz,
δ
59.5, 70.0, 81.6, 115.0, 118.2, 120.6, 121.9, 127.4, 128.0, 128.6, 128.8, 129.6, 133.6, 136.8, 137.7,
+
1
29
23
4
4
35.1584.
Synthesis of trans-3-(4-methylbenzoyl)-2-phenylchroman-4-one (2g): Product obtained as a white solid
◦
−1
in 80% [39]. m.p.: 167 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3041, 2917, 1695, 1672, 1605,1579,
f
1
1
476, 1448, 1340, 1237, 1026. H-NMR (400 MHz, CDCl ):
δ
2.39 (s, 3 H), 5.14 (d, J = 12.0 Hz, 1 H),
7.12 (m, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.31 7.37 (m, 3 H), 7.50 7.60
m, 3 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.96 (dd, J =8.0 Hz, J = 2.0 Hz 1 H). C-NMR (100 MHz, CDCl ):
3
6
(
.02 (d, J = 12.0 Hz, 1 H), 7.09
−
−
−
13
3
2
1.7, 59.5, 81.9, 118.2, 120.6, 121.9, 127.4, 128.7, 129.1, 129.3, 135.2, 136.7, 137.2, 144.6, 161.2, 189.9, 195.5.
+
HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 343.1329. Found: 343.1338.
23
19
3
Synthesis of trans-2-(4-fluorophenyl)-3-(4-methylbenzoyl)chroman-4-one (2h): Product obtained as a
◦
−1
white solid in 93%. m.p.: 133–134 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3046, 2917, 1699,
f
1
1
664, 1604, 1580, 1514, 1462, 1345, 1302, 1226, 1030. H-NMR (400 MHz, CDCl ):
δ
2.40 (s, 3 H), 5.09 (d,
3
J = 12.0 Hz, 1 H), 6.00 (d, J = 12.0 Hz, 1 H), 7.01–7.13 (m, 4 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.48–7.52 (m,

Molecules 2020, 25, 397
10 of 16
2
H), 7.56–7.60 (m, 1 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.96 (dd, J = 8.0 Hz, J = 2.0 Hz 1 H). 13C-NMR (100
MHz, CDCl3):
δ 21.7, 59.6, 81.2, 115.6 and 115.8 (d, J = 22 Hz), 118.1, 120.6, 122.1, 127.5, 128.7, 129.2
and 129.3 (d, J = 8 Hz), 129.4, 133.2 and 133.2 (d, J = 3 Hz), 135.2, 136.7, 144.9, 161.1, 161.6 and 164.1 (d,
J = 247 Hz), 189.7, 195.4. HRMS (ESI-TOF) m/z [M H] Calculated for C H FO : 359.1089. Found:
59.1075.
−
23
16
3
3
Synthesis of trans-2-(4-methoxyphenyl)-3-(4-methylbenzoyl)chroman-4-one (2i): Product obtained as a
◦
−1
white solid in 77%, m.p.: 131–133 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3030, 2836, 1693,
f
1
1
673, 1603, 1584, 1515, 1456, 1348, 1259, 1235, 1086, 1029. H-NMR (400 MHz, CDCl ):
δ
2.40 (s, 3 H),
3
3
(
.78 (s, 3 H), 5.12 (d, J = 12.0 Hz, 1 H), 5.95 (d, J = 12.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 2 H), 7.07–7.11
m, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.55–7.58 (m, 1 H), 7.74 (d, J = 8.0 Hz, 2
H), 7.94 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
21.7, 55.3, 59.4, 81.6, 114.1,
18.2, 120.6, 121.8, 127.4, 128.7, 128.8, 129.3, 129.4, 135.3, 136.6, 144.6, 159.9, 161.3, 190.2, 195.6. HRMS
δ
1
+
(ESI-TOF) m/z [M + H] Calculated for C H O : 373.1434. Found: 373.1435.
24 21 4
Synthesis of trans-2-(2-chlorophenyl)-3-(4-methylbenzoyl)chroman-4-one (2j): Product obtained as a
◦
−1
white solid in 97%. m.p.: 175–176 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3036, 2971, 1658,
f
1
1
1
601, 1573, 1470, 1459, 1230, 1026, 755. H-NMR (400 MHz, CDCl ):
δ
2.41 (s, 3 H), 5.42 (d, J = 12.0 Hz,
3
H), 6.43 (d, J = 12.0 Hz, 1 H), 7.09–7.13 (m, 2 H), 7.23–7.27 (m, 4 H), 7.41–7.47 (m, 2 H), 7.57–7.61 (m, 1
H), 7,87 (d, J = 8.0 Hz, 2 H), 7,94 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
2
1.7, 57.6, 78.4, 118.0, 120.4, 121.9, 127.2, 127.4, 128.8, 128.9, 129.4, 130.3, 130.6, 134.1, 134.3, 134.8, 136.8,
1
3
44.8, 161.2, 189.3, 194.4. HRMS (ESI-TOF) m/z [M H] Calculated for C H ClO : 375.0793. Found:
75.0786.
−
23
16
3
Synthesis of trans-3-(4-chlorobenzoyl)-2-phenylchroman-4-one (2k): Product obtained as a white solid
◦
−1
in 63% [40]. m.p.: 166–167 C. R : 0.7 (ethyl acetate/hexane 3:7). IR (cm ): 3054, 2904, 1686, 1658, 1602,
f
1
1
580, 1500, 1462, 1272, 1040, 755. H-NMR (400 MHz, CDCl ):
δ
5.07 (d, J = 12.0 Hz, 1 H), 5.97 (d,
3
J = 12.0 Hz, 1 H), 7.07–7.11 (m, 2 H), 7.30–7.38 (m, 5 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.54–7.59 (m, 1 H),
.72 (d, J = 8.0 Hz, 2 H), 7,93 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
60.0, 82.0, 118.4,
20.7, 121.1, 122.2, 127.5, 127.6, 129.0, 129.2, 129.4, 130.2, 136.2, 137.1, 137.3, 161.5, 189.8, 195.1. HRMS
7
δ
1
+
(ESI-TOF) m/z [M + H] Calculated for C H ClO : 363.0782. Found: 363.0790.
22 16 3
Synthesis of trans-3-(4-methoxybenzoyl)-2-phenylchroman-4-one (2l): Product obtained as a white
◦
−1
solid in 62% [40]. m.p.: 124–126 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3063, 2843, 1691,
f
1
1
670, 1602, 1572, 1509, 1452, 1264, 1236 1064, 1025. H-NMR (400 MHz, CDCl ):
δ
3.85 (s, 3 H), 5.11 (d,
3
J = 12.0 Hz, 1 H), 6.02 (d, J = 12.0 Hz, 1 H), 6.89 (d, J = 8.0 Hz, 2 H), 7.09–7.12 (m, 2 H), 7.30–7.37 (m, 3
H), 7.50–7.52 (m, 2 H), 7.57–7.60 (m, 1 H), 7.81 (d, J = 8.0 Hz, 2 H), 7,96 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H).
13
C-NMR (75 MHz, CDCl3):
δ 55.5, 59.3, 81.9, 113.8, 118.2, 120.7, 121.9, 127.3, 127.4, 128.7, 129.1, 130.8,
1
31.1, 136.7, 137.3, 161.3, 163.9, 189.9, 194.1. EI m/z: 260 (100%), 247 (50%), 203 (70%), 189 (30%), 130
+
(20%), 91 (40%). HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 359.1278. Found: 359.1272.
23 19 4
Synthesis of trans-3-(4-methoxybenzoyl)-2-(4-methoxyphenyl)chroman-4-one (2m): Product obtained
◦
−1
as a white solid in 96%. m.p.: 139–140 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3032, 2836, 1689,
f
1
1
672, 1599, 1571, 1510, 1454, 1265, 1251, 1230, 1072, 1037, 1019. H-NMR (400 MHz, CDCl ):
δ
3.78 (s,
3
3
H), 3.86 (s, 3 H), 5.10 (d, J = 12.0 Hz, 1 H), 5.96 (d, J = 12.0 Hz, 1 H), 6.85–6.91 (m, 4 H), 7.07–7.11
(
m, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.54–7.58 (m, 1 H), 7.83 (d, J = 8.0 Hz, 2 H), 7.95 (d, J = 8.0 Hz, 1
13
H). C-NMR (100 MHz, CDCl3):
29.4, 130.8, 131.1, 136.6, 159.9, 161.3, 163.9, 190.2, 194.2. HRMS (ESI-TOF) m/z [M + H] Calculated for
C H O : 389.1384. Found: 389.1369.
δ 55.3, 55.3, 59.2, 81.6, 113.8, 114.1, 118.2, 120.6, 121.8, 127.4, 128.8,
+
1
24
21
5
Synthesis of trans-2-(4-fluorophenyl)-3-(4-methoxybenzoyl)chroman-4-one (2n): Product obtained as a
◦
−1
white solid in 54%. m.p.: 134–135 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3063, 2916, 1689,
f
1
1
664, 1596, 1580, 1515, 1446, 1419, 1263, 1230, 1053, 1019. H-NMR (400 MHz, CDCl ):
δ
3.86 (s, 3
3
H), 5.04 (d, J = 12.0 Hz, 1 H), 6.00 (d, J = 12.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 7.01–7.13 (m, 4 H),

Molecules 2020, 25, 397
11 of 16
7
.48–7.52 (m, 2 H), 7.56–7.60 (m, 1 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.96 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H).
1
3
C-NMR (75 MHz, CDCl3):
δ 55.6, 59.4, 81.2, 113.9, 115.6 and 115.8 (d, J = 22 Hz), 118.1, 120.6, 122.0,
1
1
3
27.5, 129.2 and 129.3 (d, J = 9 Hz), 130.7, 131.1, 133.2 and 133.3 (d, J = 3 Hz), 136.7, 161.1, 161.6 and
−
64.1 (d, J = 296 Hz), 164.0, 189.8, 193.9. HRMS (ESI-TOF) m/z [M
75.1038. Found: 375.1052.
−
H] Calculated for C H FO :
23
16
4
Synthesis of trans-2-(2-chlorophenyl)-3-(4-methoxybenzoyl)chroman-4-one (2o): Product obtained
◦
−1
as a white solid in 79%. m.p.: 173–175 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3061, 2837,
f
1
1
696, 1651, 1597, 1571, 1457, 1430, 1265, 1230, 1056, 1032, 766. H-NMR (400 MHz, CDCl ):
δ
3.88 (s,
3
3
H), 5.38 (d, J = 12.0 Hz, 1 H) 6.43 (d, J = 12.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 2 H), 7.09–7.12 (m, 2
13
H), 7.23–7.28 (m, 2 H), 7.41–7.47 (m, 2 H), 7.56–7.61 (m, 1 H), 7.90–7.96 (m, 3 H). C-NMR (100 MHz,
CDCl3): 55.6, 57.4, 78.4, 113.9, 118.0, 120.5, 121.9, 127.1, 127.5, 128.8, 130.3, 130.6, 131.3, 134.1, 134.4,
36.8, 161.2, 164.0, 189.4, 193.1. EI m/z: 260 (100%), 247 (50%), 203 (70%), 189 (30%), 130 (20%), 91 (40%).
δ
1
+
HRMS (ESI-TOF) m/z [M + H] Calculated for C H ClO : 393.0888. Found: 393.0898.
23
18
4
Synthesis of trans-3-benzoyl-6-methoxy-2-phenylchroman-4-one (2p): Product obtained as a white
◦
−1
solid in 93%. m.p.: 164–165 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3043, 2841, 1697, 1669,
f
1
1
619, 1594, 1572, 1487, 1275, 1225, 1062, 1037. H-NMR (400 MHz, CDCl ):
δ
3.84 (s, 3 H), 5.14 (d,
3
J = 12.0 Hz, 1 H), 5.97 (d, J = 12.0 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 7.18–7.21 (m, 1 H), 7.30–7.37 (m, 5
H), 7.40–7.45 (m, 3 H), 7,49–7.56 (m, 3 H), 7.79–7.81 (m, 2 H). 13C-NMR (100 MHz, CDCl3):
55.9, 59.7,
2.1, 107.5, 119.5, 120.4, 126.0, 127.4, 127.8, 128.6, 128.6, 128.7, 129.1, 133.5, 137.2, 154.4, 156.0, 189.9,
δ
8
+
1
96.3. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 359.1258. Found: 359.1266.
23 19 4
Synthesis of trans-3-benzoyl-6-methoxy-2-(4-methoxyphenyl)chroman-4-one (2q): Product obtained as
◦
−1
a white solid in 92%, m.p.: 162–163 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3058, 2836,1692,
f
1
1
675, 1613, 1580, 1514, 1486, 1275, 1249, 1225, 1076, 1029. H-NMR (400 MHz, CDCl ):
δ
3.70 (s, 3 H),
3
3
.83 (s, 3 H), 5.12 (d, J = 12.0 Hz, 1 H), 5.90 (d, J = 12.0 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 2 H), 7.02 (d,
J = 8.0 Hz, 1 H), 7.17–7.18 (m, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.41–7.45 (m, 4 H), 7.54–7.58 (m, 1 H), 7.82
d, J = 8.0 Hz, 2 H). 13C-NMR (100 MHz, CDCl3):
55.3, 55.8, 59.6, 81.7, 107.5, 114.1, 119.5, 120.4, 125.9,
28.5, 128.6, 128.7, 128.6, 133.5, 137.7, 154.3, 156.1, 159.9, 190.2 196.4. HRMS (ESI-TOF) m/z [M + H]+
Calculated for C H O : 389.1345. Found: 389.1354.
(
δ
1
24
21
5
Synthesis of trans-3-benzoyl-2-(4-fluorophenyl)-6-methoxychroman-4-one (2r): Product obtained as a
◦
−1
white solid in 88%, m.p.: 125–126 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3046, 2841, 1689,
f
1
1
669, 1600, 1582, 1512, 1487, 1345, 1277, 1230, 1082, 1031. H-NMR (400 MHz, CDCl ):
δ
3.84 (s, 3 H),
3
5
.08 (d, J = 12.0 Hz, 1 H), 5.94 (d, J = 12.0 Hz, 1 H), 7.00–7.05 (m, 3 H), 7.18–7.21 (m,1 H), 7.36 (d,
13
J = 8.0 Hz, 1 H), 7.41–7.51 (m, 4 H), 7.54–7.58 (m, 1 H), 7.80 (d, J = 8.0 Hz, 2 H). C-NMR (100 MHz,
CDCl3): 55.9, 59.8, 81.4, 107.5, 115.6 and 115.8 (d, J= 22 Hz), 119.5, 120.4, 126.1, 128.6, 128.7, 129.2 and
29.3 (d, J = 8 Hz), 133.2 and 133.2 (d, J = 3 Hz). 133.7, 137.6, 154.5, 155.9, 161.6 and 164.1 (d, J = 263 Hz).
89.7, 196.2; HRMS (ESI-TOF) m/z [M − H] Calculated for C H FO : 3675.1038. Found: 375.1027.
δ
1
1
23
16
4
Synthesis of trans-3-benzoyl-2-(2-chlorophenyl)-6-methoxychroman-4-one (2s): Product obtained as a
◦
−1
white solid in 89%, m.p.: 143–144 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3069, 2846, 1685,
f
1
1
655, 1617, 1594, 1576, 1485, 1295, 1270, 1071, 1032, 760. H-NMR (400 MHz, CDCl ):
δ
3.83 (s, 3 H),
3
5
7
.41 (d, J = 12.0 Hz, 1 H), 5.38 (d, J = 12.0 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 7.18–7.27 (m, 1 H),
.23–7.27 (m, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.40–7.48 (m, 4 H), 7.56–7.60 (m, 1 H), 7.90 (d, J = 8.0
13
Hz, 2 H). C-NMR (100 MHz, CDCl3):
28.8, 130.4, 130.6, 133.7, 134.1, 134.2, 137.2, 154.4, 155.9, 189.4, 195.3. HRMS (ESI-TOF) m/z [M + H]+
Calculated for C H ClO : 393.0849. Found: 393.0888.
δ 55.9, 57.8, 78.5, 107.5, 119.4, 120.3, 126.1, 127.1, 128.5, 128.7,
1
23
18
4
Synthesis of trans-3-benzoyl-6-chloro-2-phenylchroman-4-one (2t): Product obtained as a white solid
◦
−1
in 87% [40]. m.p.: 138–139 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3039, 2895, 1697, 1672, 1600,
f
1
1
579, 1470, 1450, 1275, 1042, 760. H-NMR (400 MHz, CDCl ):
δ
5.15 (d, J = 12.0 Hz, 1 H), 6.00 (d,
3
J = 12.0 Hz, 1 H), 7.07 (d, J = 8.0 Hz, 1 H), 7.31–7.44 (m, 5 H), 7.47–7.58 (m, 4 H), 7.80 (d, J = 8.0 Hz, 2

Molecules 2020, 25, 397
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H), 7.91 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
59.3, 82.1, 119.9, 121.3, 126.6, 127.3, 127.5,
1
28.6, 128.7, 128.8, 129.3, 133.8, 136.6, 136.7, 137.4, 159.6, 188.9, 195.6. HRMS (ESI-TOF) m/z [M
−
H]
Calculated for C H ClO : 361.0637. Found: 361.0644.
22
14
3
Synthesis of trans-3-benzoyl-6-chloro-2-(4-methoxyphenyl)chroman-4-one (2u): Product obtained as a
◦
−1
white solid in 76%, m.p.: 172 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3079, 2832, 1698, 1672,
f
1
1
600, 1582, 1513, 1465, 1254, 1220, 1053, 1026, 760. H-NMR (400 MHz, CDCl ):
δ
3.78 (s, 3 H), 5.12 (d,
3
J = 12.0 Hz, 1 H), 5.92 (d, J = 12.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.40–7.59
13
(
m, 6 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.90 (d, J = 8.0 Hz, 1 H). C-NMR (100 MHz, CDCl3):
δ 55.3, 59.2,
8
1.8, 114.2, 119.96, 121.3, 126.6, 127.4, 128.6, 128.7, 128.8, 128.8, 133.7, 136.5, 137.4, 159.7, 160.1, 189.1,
+
1
95.7. HRMS (ESI-TOF) m/z [M + H] Calculated for C H ClO : 393.0888. Found: 393.0898.
23 18 4
Synthesis of trans-3-(furan-2-carbonyl)-2-phenylchroman-4-one (2v): Product obtained as a white solid
◦
−1
in 95% [41]. m.p.: 175–176 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3094, 2897, 1686, 1657, 1602,
f
1
1
570, 1502, 1459, 1248, 1146, 1045. H-NMR (400 MHz, CDCl ):
δ
4.92 (d, J = 12.0 Hz, 1 H), 5.94 (d,
3
J = 12.0 Hz, 1 H), 6.53 (d, J = 4.0 Hz, 1 H), 7.03
−
7.14 (m, 4 H), 7.17 (d, J = 4.0 Hz, 1 H), 7.49 7.60 (m, 5
−
H), 7.95 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl ):
δ
60.5, 60.57, 80.7, 112.9, 115.6, 115.9, 118.1,
3
+
1
20.5, 122.1, 127.5, 129.4, 132.9, 136.8, 147.3, 152.9, 161.1, 183.6, 189.1. HRMS (ESI-TOF) m/z [M + H]
Calculated for C H O : 319.0965. Found: 319.0976.
20
15
4
Synthesis of trans-3-(furan-2-carbonyl)-2-(4-methoxyphenyl)chroman-4-one (2w): Product obtained as
◦
−1
a white solid in 91%. m.p.: 159–160 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3095, 2841, 1695,
f
1
1
655, 1606, 1578, 1513, 1462, 1297, 1255, 1170, 1048, 1029. H-NMR (400 MHz, CDCl ):
δ
3.80 (s, 3 H),
3
4
7
.96 (d, J = 12.0 Hz, 1 H), 5.90 (d, J = 12.0 Hz, 1 H), 6.51 (d, J = 4.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 2 H),
.08 7.12 (m, 2 H), 7.17 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.55 7.57 (m, 2 H), 7.96 (d, J 8.0
55.3, 60.4, 81.1, 112.8, 114.1, 118.2, 118.5, 120.5, 121.9, 127.4,
28.8, 128.9, 136.6, 147.1, 153.1, 160.1, 161.3, 183.0, 189.5. HRMS (ESI-TOF) m/z [M H] Calculated for
C H O : 347.0925. Found: 347.0921.
−
−
1
3
Hz, 1 H). C-NMR (100 MHz, CDCl3):
1
δ
−
21
15
5
Synthesis of trans-2-(4-fluorophenyl)-3-(furan-2-carbonyl)chroman-4-one (2x): Product obtained as a
◦
−1
white solid in 90%. m.p.: 171
1
−
172 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3096, 2886, 1698,
f
1
650, 1603, 1584, 1519, 1454, 1305, 1226, 1151, 1042. H-NMR (400 MHz, CDCl ):
δ
4.94 (d, J = 12.0 Hz,
3
1
H), 5.94 (d, J = 12.0 Hz, 1 H), 6.53 (dd, J = 16.4 Hz, J = 3.5 Hz, 1 H), 7.03
−
7.14 (m, 4 H), 7.17 (d,
J = 4.0 Hz, 1 H), 7.49
δ
−
7.60 (m, 4 H), 7.96 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl ):
3
60.5, 80.7, 112.9, 115.6 and 115.9 (d, J= 22 Hz), 118.1, 118.6, 120.5, 122.1, 127.5, 129.3, 129.4 (d, J = 8
Hz), 132.8 and 132.9 (d, J= 3 Hz), 136.7, 147.3, 152.9, 161.1, 161.7 and 164.3 (d, J= 246 Hz), 183.6, 18.1.
HRMS (ESI-TOF) m/z [M − H] Calculated for C H FO : 335.0725. Found: 335.0758.
20
12
4
Synthesis of trans-3-benzoyl-2-(furan-2-yl)chroman-4-one (2y): Product obtained as a white solid in
◦
−1
2
1
4%. m.p.: 151–153 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3033, 2860, 1605, 1592, 1546, 1508,
f
1
468, 1026. H-NMR (400 MHz, CDCl ):
δ
6.24 (s, 1 H), 6.27
−
6.28 (m, 1 H), 6.34 6.35 (m, 1 H), 6.90 (d,
7.45 (m, 8 H), 7.95 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H). C-NMR
−
3
13
J = 8.0 Hz, 1 H), 7.04
−
7.09 (m, 1 H), 7.40
−
(
100 MHz, CDCl3):
δ 70.7, 103.0, 110.4, 111.4, 117.8, 120.7, 121.9, 126.3, 127.7, 128.6, 131.3, 134.5, 135.5,
+
1
43.6, 153.0, 157.0, 181.3, 182.7. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O : 319.0965.
20
15
4
Found: 319.0956.
Synthesis of trans-3-benzoyl-2-(5-nitrofuran-2-yl)chroman-4-one (2z): Product obtained as a white
◦
−1
solid in 32%. m.p.: 126–127 C. R : 0.6 (ethyl acetate/hexane 3:7). IR (cm ): 3122, 2876, 1611, 1593,
f
1
1
(
524, 1495, 1464, 1356, 1141. H-NMR (400 MHz, CDCl ):
δ
6.32 (s, 1 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.99
3
13
d, J = 8.0 Hz, 1 H), 7.10–7.17 (m, 3 H), 7.45–7.56 (m, 6 H), 7.96 (d, J = 8.0 Hz, 1 H). C-NMR (100 MHz,
CDCl3): 70.3, 101.3, 111.7, 113.6, 117.9, 120.2, 122.8, 126.5, 127.4, 128.9, 131.7, 134.0, 136.1, 155.9, 156.5,
80.7, 184.0. HRMS (ESI-TOF) m/z [M − H] Calculated for C H NO : 362.0670. Found: 362.0673.
δ
1
20
12
6

Molecules 2020, 25, 397
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Synthesis of trans-3-benzoyl-2-methylchroman-4-one (
3
): Product obtained as a white solid in 25% [41].
◦
−1
m.p.: 90–91 C. R : 0.7 (ethyl acetate/hexane 3:7). IR (cm ): 3060, 2842, 1702, 1674, 1605, 1577, 1517,
f
1
1
449, 1370, 1222, 1072. H-NMR (400 MHz, CDCl ):
δ
1,52 (d, J = 8.0 Hz, 3 H), 4.67 (d, J = 12.0 Hz, 1
3
H), 5.07–5.15 (m, 1 H), 7.04–7.08 (m, 2 H), 7.52–7.54 (m, 3 H), 7.63–7.67 (m, 1 H), 7.90 (d, J = 8.0 Hz, 1
H), 8.00 (d, J = 8.0 Hz, 2 H). 13C-NMR (100 MHz, CDCl3):
19.9, 59.9, 76.2, 117.9, 120.6, 121.6, 127.3,
28.8, 133.8, 136.5, 137.7, 161.3, 190.1, 196.1. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O :
δ
+
1
17
15
3
2
67.1016. Found: 267.1004.
3
.3. Synthesis of 3-Benzoyl-3-ethyl-2-phenylchroman-4-one (4)
Compound 2a (1 mmol), anhydrous potassium carbonate (2 mmol) and iodoethane (1.5 mmol)
◦
were added to a round bottom flask containing acetone (15 mL) and stirred at 50 C for 18 h. Upon
completion, a liquid–liquid extraction was performed with ethyl acetate (2
20 mL). The organic layer was worked up in the usual way the product was purified by flash column
chromatography, eluting with ethyl acetate and hexane. Product obtained as a yellow oil in 5% yield.
×
20 mL) and water
(
−
1
R : 0.5 (ethyl acetate/hexane 5:95). IR (cm ): 3065, 2851, 1776, 1732, 1672, 1606, 1568, 1503, 1466, 1456,
f
1
1
(
244 e 1069. H-NMR (400 MHz, CDCl ):
δ
0.93 (t, 3 H), 3.62–3.79 (m, 2 H), 6.46 (s, 1 H), 6.90–6.96
3
13
m, 2 H), 7.21–7.28 (m, 4 H), 7.40–7.47 (m, 5 H), 7.51–7.54 (m, 1 H), 7.84 (d, J = 8.0 Hz, 2 H). C-NMR
100 MHz, CDCl3): 15.1, 70.8, 77.5, 116.22, 117.2, 119.5, 121.4, 124.4, 127.1, 128.1, 128.3, 128.4, 129.1,
32.4, 132.5, 138.9, 139.8, 155.4, 155.7, 194.5. HRMS (ESI-TOF) m/z [M + H] Calculated for C H O :
24 21 3
(
1
δ
+
3
57.1484. Found: 357.1482.
3
.4. Synthesis of 3,4-diphenyl-1,4-dihydrochromeno[4,3-c]pyrazole (5)
Compound 2a (1 mmol), hydrazine (2 mmol), sodium acetate (2 mmol), and ethanol (10 mL) were
◦
added to a round bottom flask (50 mL) and stirred for 24 h at 70 C. Next, the reaction as cooled and a
liquid–liquid extraction was performed with ethyl acetate (2
was concentrated on the rotary evaporator and purified by column chromatography, eluting with
×
20 mL) and water (20 mL). The product
◦
ethyl acetate and hexane. Product obtained as a yellow solid in 57%. m.p.: 155–156 C. R : 0.3 (ethyl
f
−1
1
acetate/hexane 2.5:7.5). IR (cm ): 3450, 3044, 2923, 1618, 1574, 1509, 1471, 1300, 1212, 1035; H-NMR
(
400 MHz, CDCl3):
δ 6.64 (s,1 H), 6.93–7.02 (m, 2 H), 7.17–7.21 (m, 1 H), 7.26–7.36 (m, 5 H), 7.32–7.37
13
(
m, 6 H), 7.43 (d, J = 8.0 Hz, 1 H). C-NMR (100 MHz, CDCl3):
δ
75.7, 111.1, 117.4, 117.9, 122.1, 122.8,
+
1
26.6, 127.9, 128.6, 128.6, 129.0, 129.6, 129.8, 139.7, 152.3. HRMS (ESI-TOF) m/z [M + H] Calculated for
C H N O: 325.1344. Found: 325.1335.
22
17
2
3
.5. Anti-Trypanosoma cruzi Activity Assay (Amastigotes and Trypomastigotes)
The in vitro anti-T. cruzi activity was evaluated on L929 cells (mouse fibroblasts) infected with
Tulahuen strain of the parasite expressing the Escherichia coli β-galactosidase as reporter gene. Briefly,
for the bioassay, 4000 L929 cells were added to each well of a 96-well microtiter plate. After an
overnight incubation, 40,000 trypomastigotes were added to the cells and incubated for 2 h. Then, the
medium containing extracellular parasites were replaced with 200 µL of fresh medium and the plate
was incubated for an additional 48 h to establish the infection. For IC50 determination, the cells were
exposed to each synthesized compound at serial decreasing dilutions and the plate was incubated
for 96 h. After this period, 50
.5% Nonidet P40 was added to each well, and the plate was incubated for 16–20 h, after which the
absorbance at 570 nm was measured. Controls with uninfected cells, untreated infected cells, infected
cells treated with Benznidazole at 3.8 M (positive control) or DMSO 1% were used. The results
µL of 500 µM chlorophenol red beta-d-galactopyranoside (CPRG) in
0
µ
were expressed as the percentage of T. cruzi growth inhibition in compound-tested cells as compared
to the infected cells and untreated cells. The IC50 values were calculated by linear interpolation.
Quadruplicates were run in the same plate, and the experiments were repeated at least once.

Molecules 2020, 25, 397
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3
.6. In Vitro Cytotoxic Test of Trypanocidal Compounds
The active compounds were tested in vitro for determination of cellular toxicity against uninfected
®
L-929 cells using the alamarBlue dye. The cells were exposed to compounds at increasing
concentrations starting at IC50 value for T. cruzi. After 96 h of incubation with the tested compounds,
®
the alamarBlue was added and the absorbance at 570 and 600 nm measured after 4–6 h. The cell
viability was expressed as the percentage of difference in the reduction between treated and untreated
cells. IC50 values were calculated by linear interpolation, and the selectivity index (SI) was determined
based on the ratio of the IC50 value in the host cell divided by the IC50 value of the parasite.
Quadruplicates were run in the same plate, and the experiments were repeated at least once.
4
. Conclusions
In conclusion, the anti T. cruzi activity of 28 3-benzoylflavanones were evaluated in vitro against
amastigote and trypomastigote forms of parasite. Most of the evaluated compounds presented
promising activity against the intracellular forms of T. cruzi. In particular, flavanone 2z bearing a
nitrofuran moiety displayed and IC50 value was lower than the reference drug Benznidazole. For this
reason, the in vivo evaluation of the lead compound is in planning. Further investigations involving
colorimetric methods and indirect analysis by light microscopy to discern the mechanism of action of
the nitrofuran bearing flavanone are underway and will be disclosed in a follow-up report.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: G.M.D. and J.S.A. carried out the synthesis of the flavanone derivatives; P.A.S.J. and
S.M.F.M. evaluated the biological activity against T. cruzi; J.G.T. and V.M.R.D.S. conceived the project, designed the
experiments and analyzed the data, J.G.T. wrote the paper. All authors read and approved the final manuscript.
Funding: This work was supported by the Brazilian funding agency Fundação de Amparo à Pesquisa do Estado
de Minas Gerais (FAPEMIG) under research grant project code APQ-01629-16. This study was financed in part by
the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.
Acknowledgments: This work was supported by the Brazilian funding agency Fundaç
do Estado de Minas Gerais (FAPEMIG) under research grant project code APQ-01629-16. This study was financed
in part by the Coordenaç o de Aperfeiçoamento de Pessoal de N vel Superior—Brasil (CAPES)—Finance Code
01. Authors gratefully acknowledge the generous financial support from the Universidade Federal de Ouro
Preto (UFOP), FAPEMIG, and the Conselho Nacional de Desenvolvimento Cient fico e Tecnol gico (CNPq). The
ão de Amparo à Pesquisa
ã
í
0
í
ó
authors thank the Program for Technological Development of Tools for Health-PDTIS-FIOCRUZ for use of its
facilities. The authors would also like to thank Robson Jose de Cassia Afonso (UFOP) and Ananda Lima Sanson
(
UFOP) for the excellent mass spectrometry service. Policarpo Ademar Sales Junior is research fellow supported
by Programa de P s-graduaç o em Ci ncias da Sa de, Fiocruz Minas (CAPES/PNPD). The authors would also
rio Multiusu rio de Caracterizaç o de Mol culas (UFOP) for excellent Nuclear Magnetic
ó
ã
ê
á
ú
like to thank the Laborat
Resonance service.
ó
ã
é
Conflicts of Interest: The authors declare no conflict of interest.
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